1) Field of the Invention
The present invention relates to therapeutic agents for myocardial ischemic damages or reperfusion injuries which have excellent action for restoring heart functions lowered by myocardial ischemia or reflow.
2) Background Art
In open heart surgery including heart transplant, an aortic blockade is useful and even essential since it provides an excellent setting in terms of surgical techniques, including a bloodless and stationary field of view.
However, due to the stoppage of coronary blood flow during an operation, myocardial cells rapidly become to undergo anaerobic metabolism in which energy production efficiency is very poor. Subsequently, accumulation of lactic acid and hydrogen ions generated in the course of anaerobic metabolism reduces pH in tissues and suppresses oxidation of fatty acids, thereby causing damage to mitochondria. As a result, myocardial cells have disorders in energy-dependent cell membrane functions, and these disorders impair the equilibration ability and cell capacity maintenance ability of cytoplasms. In addition, calcium ions abnormally flow into cells, inviting sodium ions and water into the cells. Eventually, myocardial cells come to have irreversible ischemic damages.
In order to prevent the above-mentioned myocardial ischemic damages, it is essential that high energy substances in heart muscles be retained during ischemia. Presently, a protection method for heart muscles is used which is primarily a combination of a local cooling method for heart muscles and a method of multi-administration of a myocardial preservation solution in which a myocardial preservation solution is intermittently administered to the patient.
However, this method still cannot satisfactorily prevent myocardial ischemic damages.
On the other hand, although ischemic heart muscles recover from the low energy state when an aortic blockade is removed after a heart operation, reflow of blood after ischemia is known to cause even worse disorders called reperfusion injuries. Reperfusion injuries are considered to be caused primarily by changes in membranes during ischemia which trigger the reflow. Within an early stage of 2-3 minutes from the start of reflow, abnormal transfer of calcium ions as well as sodium ions and water occurs, and oxygen radicals are generated. In order to prevent reperfusion injuries, useful compounds have been studied in adition to a careful blood flow restarting method which requires a high skill. However, successful results have not yet been obtained in preventing reperfusion injuries.
The onset of heart infarction is considered to be triggered by a repeated blockade of the coronary artery and subsequent reflow caused, for example, by atherosclerosis and thrombus. In this case, heart muscles undergo ischemic damages and reperfusion injuries. In the therapy of heart infarctions, percutaneous transluminal coronary angioplasy (PTCA) in which balloons are used for dilating the inner diameter of the coronary artery or percutaneous transluminal coronary recanalization (PTCR) in which a thrombolytic agent is administered through a catheter are adopted, and favorable results have been obtained. However, these approaches are still not free from reflow disorders.
Under the above circumstances, the present inventors conducted earnest studies to discover drugs capable of suppressing those disorders, and as a result, found that the compounds represented by the following formula (1), their acid addition salts, and their hydrates have an action of restoring heart functions which were lowered by ischemia-reflow of heart muscles, and that these compounds, salts, and hydrates are useful as therapeutic agents for myocardial ischemic damages and reperfusion injuries. The present invention was accomplished based on this finding.